Genetic signatures of dengue virus emergence

登革热(DENV)在过去25年中再次成为最重要的新发传染病之一 世界范围内的疾病，对美国构成重大的A类生物防御威胁 波多黎各的流行病，以及最近在夏威夷(2001年)和德克萨斯州(1999年、2005年、2006年)爆发的疫情。它的全球 复苏，虽然部分原因是人口结构的变化，日益严重的地方性，以及 关于蚊子媒介的扩张，人们仍然知之甚少，特别是关于病毒的重要性 进化论。我们通过对DENV毒株进行比较进化检查来填补这一关键空白 正在经历疫情扩张，来自整个亚太舞台上的复制种群，与 直接的组织和动物模型分析与流行病相关的病毒表型的变化。我们的长期合作 目标是解决病毒基因变化是如何导致疾病出现的。建议的目标是 研究是描述从流行中分离出来的登革热病毒相对于其地方性疾病的进化。 在实验模型中形成并确认基因变化的影响，其基本原理是 对这种病毒基因变化及其固定机制的识别将阐明决定因素 登革热的流行潜力和最终的发病机制。 具体目标1：确定DENV在流行和流行传播阶段之间的演变 识别具有较高流行潜力的突触。 特定目的2：确认DENV流行株的基因变化与其之间的关系 体外模型中的表型效应。 具体目标3：确认DENV流行毒株的基因变化与其 体内模型中的表型效应

Dengue (DENV) has re-emerged in the last 25 years as one of the most significant emerging infectious diseases worldwide, posing a significant category A biodefense threat to the United States with ongoing epidemics in Puerto Rico, and recent outbreaks in Hawaii (2001) and Texas (1999, 2005, 2006). Its global resurgence, while partly explained by changing human demographics, increasing hyperendemicity, and mosquito vector expansions, remains poorly understood, especially with respect to the importance of virus evolution. We fill this critical gap by conducting a comparative evolutionary examination of DENV strains undergoing epidemic expansion, from replicate populations across the Asia-Pacific arena, paired with directed tissue and animal model assays for changes in virus phenotype related to epidemics. Our long-term goal is to resolve how viral genetic change drives disease emergence. The objective of the proposed research is to characterize evolution in dengue viruses isolated from epidemics relative to their endemic forms and confirm the impact of genetic changes in experimental models, the rationale being that identification of such viral genetic changes and their mechanisms of fixation will illuminate determinants of dengue epidemic potential and ultimately pathogenesis. Specific Aim 1: Determine the evolution of DENV between endemic and epidemic transmission phases to identify synapomorphies of higher epidemic potential. Specific Aim 2: Confirm the relationship between genetic changes in DENV epidemic strains and their phenotypic effects in in vitro models. Specific Aim 3: Confirm the relationship between genetic changes in DENV epidemic strains and their phenotypic effects in in vivo models